Olmesar na 40/12.5/10
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Olmesar NA 40/12.5/5 Olmesar NA 40/12.5/10
Composition:
Active substances: olmesartan medoxomil, amlodipine besylate, hydrochlorothiazide;
One film-coated tablet contains olmesartan medoxomil 40 mg, amlodipine besylate 6.944 mg, equivalent to amlodipine 5 mg, and hydrochlorothiazide 12.5 mg
or olmesartan medoxomil 40 mg, amlodipine besylate 13.888 mg, equivalent to amlodipine 10 mg, and hydrochlorothiazide 12.5 mg;
Excipients: microcrystalline cellulose, pregelatinized starch, sodium croscarmellose, colloidal silicon dioxide, magnesium stearate;
Coating: Opadry II Yellow 85F32331 (polyvinyl alcohol, titanium dioxide (E 171), macrogol, talc, yellow iron oxide (E 172)); Opadry II Pink 85F540068 (polyvinyl alcohol – partially hydrolyzed, titanium dioxide (E 171), macrogol, talc, red iron oxide (E 172), yellow iron oxide (E 172)).
Pharmaceutical form. Film-coated tablets.
Main physico-chemical properties:
for dosage 40 mg/5 mg/12.5 mg: light-yellow, round, biconvex film-coated tablets with "T 22" engraved on one side and smooth on the other side;
for dosage 40 mg/10 mg/12.5 mg: grey-red, round, biconvex film-coated tablets with "T 24" engraved on one side and smooth on the other side.
Pharmacotherapeutic group.
Cardiovascular system. Agents acting on the renin-angiotensin system. Angiotensin II antagonists in combination with other agents. Olmesartan medoxomil, amlodipine and hydrochlorothiazide. ATC code C09DX03.
Pharmacological Properties
Pharmacodynamics
Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) is a combination medicinal product containing olmesartan medoxomil – an angiotensin II receptor antagonist, amlodipine besylate – a calcium channel blocker, and the thiazide diuretic hydrochlorothiazide. The combination of these components provides an additive antihypertensive effect, reducing arterial pressure to a greater extent than each active ingredient alone.
Olmesartan Medoxomil
Olmesartan medoxomil is an orally active, selective antagonist of angiotensin II receptors (AT1 type). Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system and plays a key role in the pathophysiology of arterial hypertension. The effects of angiotensin II include vasoconstriction, stimulation of aldosterone synthesis and release, cardiac stimulation, and renal sodium reabsorption. Olmesartan blocks the vasoconstrictive and aldosterone-secreting effects of angiotensin II by inhibiting its binding to AT1 receptors in tissues, including vascular smooth muscle and adrenal glands. The action of olmesartan is independent of the source or pathway of angiotensin II synthesis. Selective antagonism of angiotensin II receptors (AT1) by olmesartan leads to increased plasma renin levels and concentrations of angiotensin I and II, as well as a slight decrease in plasma aldosterone concentration.
In patients with arterial hypertension, olmesartan medoxomil provides sustained reduction in arterial pressure, the extent of which is dose-dependent. No signs of arterial hypotension after the first dose (first-dose effect), tachyphylaxis during prolonged use, or rebound hypertension after abrupt discontinuation of the drug have been observed.
When olmesartan medoxomil is administered once daily to patients with arterial hypertension, effective and smooth reduction in arterial pressure occurs over the 24-hour interval between doses. When administered once daily, its antihypertensive effect is approximately equivalent to that achieved with twice-daily administration at the same total daily dose.
With continuous treatment, maximum reduction in arterial pressure is achieved within 8 weeks after initiation of therapy; however, a significant antihypertensive effect is observed as early as 2 weeks of treatment.
The effect of olmesartan medoxomil on mortality and the frequency of complications has not been established.
The randomized trial of olmesartan for the prevention of diabetic microalbuminuria (ROADMAP), involving 4447 patients with type 2 diabetes mellitus with normal albuminuria levels and at least one additional cardiovascular risk factor, was conducted to determine whether olmesartan therapy could delay the onset of microalbuminuria. During a mean follow-up period of 3.2 years, patients received olmesartan or placebo in addition to other antihypertensive agents, excluding ACE inhibitors or ARBs.
In the primary endpoint of the study, a significant reduction in the risk of time to onset of microalbuminuria was demonstrated with olmesartan use. After adjusting for differences in blood pressure (BP) values, this risk reduction was no longer statistically significant. Microalbuminuria developed in 8.2% (178 out of 2160) of patients in the olmesartan group and in 9.8% (210 out of 2139) of patients in the placebo group.
In the secondary endpoint, cardiovascular events occurred in 96 patients (4.3%) receiving olmesartan and in 94 patients (4.2%) receiving placebo. Cardiovascular mortality was higher in the olmesartan group compared to the placebo group (15 patients (0.7%) vs. 3 patients (0.1%)), despite similar rates of non-fatal stroke (14 patients (0.6%) vs. 8 patients (0.4%)), non-fatal myocardial infarction (17 patients (0.8%) vs. 26 patients (1.2%)), and non-cardiovascular mortality (11 patients (0.5%) vs. 12 patients (0.5%)). Overall mortality was higher in the olmesartan group (26 patients (1.2%) vs. 15 patients (0.7%)), primarily due to higher cardiovascular mortality.
In the ORIENT trial (The Olmesartan Reducing Incidence of End-stage Renal Disease in Diabetic Nephropathy Trial), the effect of olmesartan on renal and cardiovascular outcomes was studied in 577 randomized patients in Japan and China with type 2 diabetes and overt nephropathy. During a mean follow-up period of 3.1 years, patients received olmesartan or placebo in addition to other antihypertensive agents, including ACE inhibitors.
The primary composite endpoint (time to first occurrence of doubling of serum creatinine, end-stage renal disease, or death from any cause) was reached in 116 patients in the olmesartan group (41.1%) and in 129 patients receiving placebo (45.4%) (HR 0.97 (95% CI 0.75–1.24); p = 0.791). The secondary composite cardiovascular endpoint was reached in 40 patients receiving olmesartan (14.2%) and in 53 patients receiving placebo (18.7%). This composite cardiovascular endpoint included cardiovascular death in 10 (3.5%) patients receiving olmesartan and in 3 (1.1%) patients receiving placebo; overall mortality was 19 (6.7%) and 20 (7.0%), non-fatal stroke was 8 (2.8%) and 11 (3.9%), and non-fatal myocardial infarction was 3 (1.1%) and 7 (2.5%), respectively.
Amlodipine
Amlodipine, included in the formulation, is a calcium channel blocker that inhibits transmembrane influx of calcium ions through voltage-dependent L-type channels in the heart and vascular smooth muscle. Experimental data indicate that amlodipine interacts with both dihydropyridine binding sites and other sites. Amlodipine has relative vasoselectivity and affects vascular smooth muscle cells more than cardiomyocytes. The antihypertensive effect of amlodipine is due to direct relaxation of arterial smooth muscle cells, leading to reduced peripheral vascular resistance and, consequently, reduced arterial pressure.
In arterial hypertension, amlodipine induces a dose-dependent, prolonged reduction in arterial pressure. No arterial hypotension after the first dose, signs of tachyphylaxis during prolonged therapy, or recurrence of arterial hypertension after discontinuation of treatment have been observed.
After oral administration at therapeutic doses in patients with arterial hypertension, amlodipine effectively reduces arterial pressure in supine, sitting, and standing positions. Long-term use of amlodipine is not associated with significant changes in heart rate or plasma catecholamine levels. In patients with arterial hypertension and normal renal function, amlodipine at therapeutic doses reduces renal vascular resistance and increases glomerular filtration rate and effective renal plasma flow without altering filtration fraction or inducing proteinuria.
In hemodynamic studies in patients with heart failure, as well as in clinical stress testing studies in heart failure (NYHA classes II–IV), amlodipine did not worsen patient status as assessed by exercise tolerance, left ventricular ejection fraction, or clinical signs and symptoms.
In a placebo-controlled trial (PRAISE) involving patients with heart failure (NYHA classes III–IV) receiving digoxin, diuretics, and ACE inhibitors, amlodipine was shown not to increase the risk of fatal outcome or the combined risk of mortality and morbidity in patients with heart failure.
In a subsequent long-term placebo-controlled trial (PRAISE-2) of amlodipine in patients with heart failure (NYHA III and IV) without clinical symptoms or objective evidence of ischemic heart disease, receiving ACE inhibitors, digitalis agents, and diuretics at stable doses, amlodipine did not affect overall mortality or cardiovascular-specific mortality. In this patient group, an increased incidence of pulmonary edema associated with amlodipine use was observed, but no statistically significant differences in the frequency of worsening heart failure compared to the placebo group were noted.
To compare modern therapeutic approaches, a double-blind, randomized trial assessing morbidity and mortality, titled "Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial" (ALLHAT), was conducted: amlodipine at 2.5–10 mg/day (calcium channel blocker) or lisinopril at 10–40 mg/day (ACE inhibitor) as first-line therapy, and the thiazide diuretic chlorthalidone at 12.5–25 mg/day in mild to moderate hypertension.
Overall, 33,357 patients with arterial hypertension aged 55 years or older were randomized and followed for a mean of 4.9 years. Patients had at least one additional risk factor for coronary heart disease (CHD), such as prior myocardial infarction or stroke (more than 6 months before enrollment) or other atherosclerotic cardiovascular diseases (51.5% total), type 2 diabetes (36.1%), LDL-cholesterol level < 35 mg/dL (11.6%), left ventricular hypertrophy diagnosed by electrocardiography or echocardiography (20.9%), or current smoking (21.9%).
The primary endpoint of the study was a combination of fatal CHD or non-fatal myocardial infarction. No significant differences in the primary endpoint were observed between amlodipine and chlorthalidone therapy: HR 0.98, 95% CI (0.90–1.07), p = 0.65. Regarding secondary endpoints, the incidence of heart failure (a component of the composite cardiovascular disease endpoint) was significantly higher in the amlodipine group compared to the chlorthalidone group (10.2% vs. 7.7%, HR 1.38, 95% CI [1.25–1.52], p < 0.001). However, no significant differences in all-cause mortality between amlodipine and chlorthalidone therapy were observed (HR 0.96, 95% CI [0.89–1.02], p = 0.20).
Hydrochlorothiazide
Hydrochlorothiazide is a thiazide-type diuretic. The mechanism of antihypertensive action of thiazide diuretics is not fully understood. Thiazides affect electrolyte reabsorption in renal tubules, thereby enhancing excretion of sodium and chloride (approximately at equal levels). Acting as a diuretic, hydrochlorothiazide reduces plasma volume, leading to increased plasma renin activity and aldosterone secretion, increased urinary excretion of potassium and bicarbonate, and decreased serum concentrations of these electrolytes. Since the relationship between renin levels and aldosterone secretion is mediated by angiotensin II, when hydrochlorothiazide is used in combination with an angiotensin II receptor blocker, potassium losses in urine due to thiazide diuretics may be reduced. After administration, diuresis begins approximately 2 hours later, maximum effect is achieved approximately 4 hours later, and the effect lasts for 6–12 hours.
According to epidemiological data, long-term use of hydrochlorothiazide as monotherapy reduces the risk of cardiovascular complications and death from them.
Clinical Efficacy and Safety
In a 12-week, double-blind, randomized, parallel-group study involving 2492 patients (67% were Caucasian), treatment with olmesartan medoxomil/amlodipine/hydrochlorothiazide 40 mg/10 mg/25 mg resulted in significantly greater reduction in diastolic and systolic arterial pressure compared to treatment with any of the following dual combinations: olmesartan medoxomil 40 mg plus amlodipine 10 mg, olmesartan medoxomil 40 mg plus hydrochlorothiazide 25 mg, and amlodipine 10 mg plus hydrochlorothiazide 25 mg.
The additional blood pressure-lowering effect of olmesartan medoxomil/amlodipine/hydrochlorothiazide 40 mg/10 mg/25 mg compared to the respective dual combinations was -3.8 to -6.7 mm Hg for seated diastolic blood pressure and -7.1 to -9.6 mm Hg for seated systolic blood pressure, occurring within the first 2 weeks.
The proportion of patients achieving blood pressure levels < 140/90 mm Hg for non-diabetic patients and < 130/80 mm Hg for diabetic patients at week 12 ranged from 34.9% to 46.6% in dual combination therapy groups compared to 64.3% in the olmesartan medoxomil/amlodipine/hydrochlorothiazide 40 mg/10 mg/25 mg group.
In a second double-blind, randomized, parallel-group study involving 2690 patients (99.9% were Caucasian), treatment with olmesartan medoxomil/amlodipine/hydrochlorothiazide (20 mg/5 mg/12.5 mg, 40 mg/5 mg/12.5 mg, 40 mg/5 mg/25 mg, 40 mg/10 mg/12.5 mg, 40 mg/10 mg/25 mg) showed significant reduction in diastolic and systolic arterial pressure compared to the following dual combinations: olmesartan medoxomil 20 mg plus amlodipine 5 mg, olmesartan medoxomil 40 mg plus amlodipine 5 mg, and olmesartan medoxomil 40 mg plus amlodipine 10 mg – after 10 weeks of treatment.
The additional blood pressure-lowering effect of Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) compared to the respective dual combinations was -1.3 to -1.9 mm Hg for seated diastolic blood pressure and -2.7 to -4.9 mm Hg for seated systolic blood pressure.
The proportion of patients achieving blood pressure levels < 140/90 mm Hg for non-diabetic patients and < 130/80 mm Hg for diabetic patients at week 10 was 42.7–49.6% in dual combination therapy groups compared to 52.4–58.8% in the Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) group.
In a randomized, double-blind study involving 808 patients (99.9% were Caucasian) whose blood pressure was inadequately controlled after 8 weeks of dual therapy with olmesartan medoxomil 40 mg and amlodipine 10 mg, significant additional reduction in seated blood pressure (-1.8/-1.0 mm Hg) was demonstrated with Olmesar NA 40/12.5/10, and statistically significant reduction in seated blood pressure (-3.6/-2.8 mm Hg) with olmesartan medoxomil/amlodipine/hydrochlorothiazide 40 mg/10 mg/25 mg compared to dual therapy with olmesartan medoxomil 40 mg and amlodipine 10 mg.
Treatment with the drug containing olmesartan medoxomil/amlodipine/hydrochlorothiazide 40 mg/10 mg/25 mg using a triple combination of active substances led to a statistically significant increase in the percentage of patients achieving target blood pressure compared to dual therapy with olmesartan medoxomil (40 mg) and amlodipine (10 mg) (41.3% vs. 24.2%); conversely, use of the triple combination contained in Olmesar NA 40/12.5/10 led to a numerically higher percentage of patients achieving target blood pressure compared to dual therapy with olmesartan medoxomil (40 mg) and amlodipine (10 mg) in patients who did not achieve adequate blood pressure control (29.5% vs. 24.2%).
The antihypertensive effect of Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) was independent of patient age and sex, as well as the presence or absence of diabetes mellitus.
Other Information
Concomitant use of ACE inhibitors and angiotensin II receptor blockers was studied in two large-scale randomized controlled trials (ONTARGET [ONgoing Telmisartan Alone in combination with Ramipril Global Endpoint Trial] and VA NEPHRON-D [The Veterans Affairs Nephropathy in Diabetes]).
ONTARGET was a trial involving patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes with evidence of target organ damage. VA NEPHRON-D was a trial involving patients with type 2 diabetes and diabetic nephropathy. These trials did not demonstrate a significant beneficial effect on renal and/or cardiovascular outcomes or mortality, while compared to monotherapy, there was an increased risk of hyperkalemia, acute kidney injury, and/or hypotension. Due to the similarity of pharmacodynamic properties, these results also apply to other ACE inhibitors and angiotensin II receptor blockers. Therefore, concomitant use of ACE inhibitors and angiotensin II receptor blockers is contraindicated in patients with diabetic nephropathy.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a trial conducted to assess the positive effect of adding aliskiren to standard therapy with ACE inhibitors or angiotensin II receptor blockers in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. This trial was prematurely terminated due to an increased risk of adverse outcomes. Cardiovascular death and stroke were more frequent in the aliskiren group than in the placebo group, and reports of adverse events and serious adverse events (hyperkalemia, hypotension, and renal function impairment) were more frequent in the aliskiren group than in the placebo group.
Pharmacokinetics
Concomitant administration of olmesartan medoxomil, amlodipine, and hydrochlorothiazide had no clinically significant effect on the pharmacokinetics of any component in healthy volunteers.
After oral administration of Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) in healthy adult volunteers, the maximum plasma concentration of olmesartan, amlodipine, and hydrochlorothiazide is reached approximately at 1.5–3 hours, 6–8 hours, and 1.5–2 hours, respectively. The rate and extent of absorption of olmesartan medoxomil, amlodipine, and hydrochlorothiazide are the same as when a dual fixed combination of olmesartan medoxomil and amlodipine is administered together with a single-component hydrochlorothiazide tablet or when a dual fixed combination of olmesartan medoxomil and hydrochlorothiazide is administered together with a single-component amlodipine tablet at equivalent doses. Food intake does not affect the bioavailability of the drug.
Olmesartan Medoxomil
Absorption and Distribution
Olmesartan medoxomil is a prodrug. It is rapidly converted to the pharmacologically active metabolite olmesartan by esterases in the intestinal mucosa and portal blood during absorption in the gastrointestinal tract. Unconverted olmesartan medoxomil or the medoxomil side chain group are not detected in plasma or excreted products. The mean absolute bioavailability of olmesartan in tablet form is 25.6%.
The mean maximum plasma concentration (Cmax) of olmesartan is reached approximately 2 hours after oral administration. Olmesartan plasma concentration increases approximately linearly with increasing single doses up to 80 mg.
Food has minimal effect on olmesartan bioavailability; therefore, olmesartan medoxomil can be administered regardless of food intake. No clinically significant differences in olmesartan pharmacokinetics between genders have been observed.
Olmesartan is highly bound to plasma proteins (99.7%), but the risk of clinically significant competitive interactions with other drugs that are highly plasma protein-bound is low. This is supported by the absence of interaction between olmesartan medoxomil and warfarin. Olmesartan binds minimally to blood cells. The mean volume of distribution after intravenous administration is low (16–29 L).
Metabolism and Elimination
Total plasma clearance of olmesartan is typically 1.3 L/hour (coefficient of variation 19%) and is relatively small compared to hepatic blood flow (approximately 90 L/hour). After a single oral dose of 14C-labeled olmesartan medoxomil, 10–16% of the radioactive substance is excreted in urine (mostly within 24 hours after administration), and the remainder of the recovered radioactivity is excreted in feces. Based on systemic availability (25.6%), it can be calculated that approximately 40% of olmesartan is excreted by the kidneys and 60% via the hepatobiliary system. All recovered radioactivity was attributed to olmesartan. No other significant metabolites were found. Enterohepatic recirculation of olmesartan is minimal. Since the majority of olmesartan is excreted in bile, its use is contraindicated in patients with biliary obstruction (see section "Contraindications").
The terminal elimination half-life of olmesartan after multiple oral doses ranges from 10 to 15 hours. Steady state is achieved after the first few doses, and no further accumulation is observed after 14 days of multiple dosing. Renal clearance is approximately 0.5–0.7 L/hour, independent of drug dose.
Interaction with Other Medicinal Products
The bile acid-binding drug colesevelam.
Concomitant administration of 40 mg olmesartan medoxomil and 3750 mg colesevelam hydrochloride in healthy volunteers resulted in a 28% reduction in olmesartan Cmax and a 39% reduction in AUC. A lesser effect, with 4% and 15% reduction in Cmax and AUC, respectively, was observed when olmesartan medoxomil was administered 4 hours before colesevelam hydrochloride. The elimination half-life of olmesartan was reduced by 50–52%, regardless of whether the drugs were administered together or olmesartan was administered 4 hours before colesevelam hydrochloride (see section "Interaction with Other Medicinal Products and Other Types of Interaction").
Amlodipine
Absorption and Distribution
After oral administration at therapeutic doses, amlodipine is well absorbed, with peak blood concentrations reached 6–12 hours after administration. Absolute bioavailability is approximately 64–80%. The volume of distribution is approximately 21 L/kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins.
Amlodipine absorption is not affected by concomitant food intake.
Metabolism and Elimination
The elimination half-life from plasma ranges from 35 to 50 hours and remains unchanged with daily single administration. Amlodipine is extensively metabolized to inactive metabolites. Approximately 60% of the administered dose is excreted in urine, of which 10% is unchanged.
Hydrochlorothiazide
Absorption and Distribution
After oral administration of olmesartan medoxomil and hydrochlorothiazide in combination, the mean time to reach maximum hydrochlorothiazide concentration is 1.5–2 hours. Hydrochlorothiazide is 68% bound to plasma proteins, and its apparent volume of distribution is 0.83–1.14 L/kg.
Metabolism and Elimination
Hydrochlorothiazide is not metabolized in the human body and is almost entirely excreted unchanged in urine. Approximately 60% of the oral dose is excreted unchanged within 48 hours. Renal clearance is approximately 250–300 mL/min. The terminal elimination half-life is 10–15 hours.
Pharmacokinetics in Specific Patient Groups
Elderly Patients (Aged 65 Years and Older)
It has been demonstrated that in arterial hypertension, the steady-state AUC of olmesartan increases by approximately 35% in elderly patients (aged 65–75 years) compared to younger patients and by approximately 44% in very elderly patients (≥ 75 years) (see section "Dosage and Administration").
This can be partially explained by moderate age-dependent decline in renal function in this patient group. However, the same dosing regimen is recommended for elderly patients as for other patients, although dose escalation should be done cautiously.
The time to reach maximum plasma concentration of amlodipine is the same in older and younger patients. In elderly patients, there is a tendency toward reduced amlodipine clearance, leading to increased AUC and prolonged elimination half-life. The increase in AUC and prolonged elimination half-life in patients with congestive heart failure are consistent with expectations for this age group (see section "Special Considerations").
Limited data suggest that systemic clearance of hydrochlorothiazide is reduced in healthy elderly patients with hypertension compared to young healthy volunteers.
Children
The European Medicines Agency has waived the obligation to submit results of studies of Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) in all subgroups of pediatric patients with essential hypertension.
Renal Impairment
In patients with mild, moderate, and severe renal impairment, the steady-state AUC of olmesartan was 62%, 82%, and 179% higher, respectively, compared to healthy volunteers. The elimination half-life of hydrochlorothiazide is prolonged in patients with renal impairment.
The pharmacokinetics of olmesartan medoxomil in patients undergoing hemodialysis has not been studied.
Amlodipine is extensively metabolized to inactive metabolites. 10% of the drug is excreted unchanged in urine. Changes in amlodipine plasma concentration do not correlate with the degree of renal impairment. Amlodipine can be administered at usual doses to such patients. Amlodipine is not removed by dialysis.
The elimination half-life of hydrochlorothiazide is prolonged in patients with renal impairment.
Hepatic Impairment
After a single oral dose, AUC values of olmesartan were 6% and 65% higher, respectively, in patients with mild or moderate hepatic impairment compared to healthy volunteers. The unbound fraction of olmesartan 2 hours after administration in healthy volunteers and patients with mild or moderate hepatic impairment was 0.26%, 0.34%, and 0.41%, respectively.
After repeated administration, the mean AUC of olmesartan in patients with moderate hepatic impairment was 65% higher than in healthy volunteers. Mean Cmax values of olmesartan in patients with hepatic impairment and healthy volunteers were similar (see sections "Dosage and Administration", "Special Considerations").
Clinical data on amlodipine use in patients with hepatic impairment are very limited. In patients with hepatic impairment, reduced amlodipine clearance and prolonged elimination half-life are observed, leading to an increase in AUC by approximately 40–60% (see sections "Dosage and Administration", "Special Considerations").
Hepatic insufficiency does not significantly affect the pharmacokinetics of hydrochlorothiazide.
Preclinical Safety Data
Repeat-dose toxicity studies in rats showed that combined administration of olmesartan medoxomil, amlodipine, and hydrochlorothiazide did not enhance any previously recorded or existing toxic effects of individual components and did not cause any new toxicity. No toxicological synergistic effects were observed.
No additional studies on mutagenicity, carcinogenicity, or reproductive toxicity were conducted for Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) due to the well-understood safety profile of individual active components.
Olmesartan Medoxomil
In chronic toxicity studies in rats and dogs, effects of olmesartan medoxomil were similar to those of other AT1 receptor antagonists and ACE inhibitors: increased blood urea nitrogen (BUN) and creatinine levels, reduced heart weight, reduced erythrocyte parameters (erythrocyte count, hemoglobin, hematocrit), and histological signs of kidney damage (regenerative kidney epithelial injury, thickening of the basement membrane, tubular dilation). These adverse reactions, caused by the pharmacological action of olmesartan medoxomil, were also observed in preclinical studies with other AT1 receptor antagonists and ACE inhibitors and can be reduced by adding sodium chloride orally.
Similar to other AT1 receptor antagonists, olmesartan medoxomil increases the frequency of chromosomal breaks in in vitro cell cultures. This effect was not observed in several in vivo studies where olmesartan medoxomil was administered orally at very high doses up to 2000 mg/kg. Overall, comprehensive genotoxicity study results suggest that genotoxic effects of olmesartan in clinical use are unlikely.
No carcinogenic effect of olmesartan medoxomil was observed in rats and transgenic mice.
In reproductive toxicity studies in rats, olmesartan medoxomil did not affect fertility and had no teratogenic effect. As with other angiotensin II receptor antagonists, offspring survival was reduced after exposure to olmesartan medoxomil, and female rats receiving the drug in late pregnancy and during lactation showed dilatation of renal pelvises. No fetotoxic effect was observed in rabbits.
Amlodipine
Reproductive Toxicity
Reproductive function studies in rats and mice showed delayed delivery, prolonged labor, and reduced offspring survival at doses approximately 50 times higher than the maximum recommended human dose based on body weight (mg/kg).
Fertility Impairment
No effect on fertility was observed in rats (males for 64 days, females for 14 days before mating) receiving amlodipine at doses up to 10 mg/kg/day (8 times the maximum recommended human dose of 10 mg based on mg/m², assuming a patient body weight of 50 kg). In another study, male rats receiving amlodipine besylate for 30 days at doses comparable to human doses based on mg/kg showed reduced plasma levels of follicle-stimulating hormone and testosterone, reduced sperm density, and decreased numbers of mature spermatids and Sertoli cells.
Carcinogenesis, Mutagenesis
Two-year carcinogenicity studies in rats and mice receiving amlodipine in diet at concentrations calculated to achieve daily doses of 0.5, 1.25, and 2.5 mg/kg/day showed no signs of carcinogenicity. The highest dose (equivalent to the maximum recommended dose of 10 mg based on mg/m² in mice and twice the maximum recommended dose in rats) was close to the maximum tolerated dose in mice but not in rats.
Mutagenicity studies showed no drug-related effects at the gene or chromosome level.
Hydrochlorothiazide
Non-melanoma Skin Cancer
Available epidemiological data indicate a cumulative dose-dependent relationship between hydrochlorothiazide use and the development of non-melanoma skin cancer. In a study involving 1,430,833 and 172,462 individuals, 71,533 cases of basal cell carcinoma and 8,629 cases of squamous cell carcinoma were recorded. High-dose hydrochlorothiazide use (≥ 50,000 mg cumulative) was associated with an adjusted risk ratio of 1.29 (95% CI: 1.23–1.35) for basal cell carcinoma and 3.98 (95% CI: 3.68–4.31) for squamous cell carcinoma. A clear cumulative dose effect was observed for both basal cell and squamous cell carcinoma. Another study showed a possible link between lip cancer (squamous cell carcinoma of the skin) and hydrochlorothiazide exposure: 633 cases of lip cancer in a study involving 63,067 individuals using a risk-set sampling strategy. A cumulative dose effect was demonstrated with an adjusted risk ratio of 2.1 (95% CI: 1.7–2.6), increasing to 3.9 (3.0–4.9) with high-dose use (~25,000 mg) and to 7.7 (5.7–10.5) with the highest cumulative dose (~100,000 mg) (see section "Special Considerations").
Clinical characteristics.
Indications.
Treatment of essential hypertension.
Additional therapy.
Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) is indicated in adult patients whose blood pressure is not adequately controlled with a combination of olmesartan medoxomil and amlodipine as a two-component medicinal product.
Substitution therapy.
Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) is indicated as an alternative therapy in adult patients whose blood pressure is well controlled with a combination of olmesartan medoxomil, amlodipine, and hydrochlorothiazide as two-component medicinal products (olmesartan medoxomil and amlodipine or olmesartan medoxomil and hydrochlorothiazide) and single-component medicinal products (hydrochlorothiazide or amlodipine).
Contraindications.
- Hypersensitivity to the active substances, to dihydropyridine derivatives, or to sulfonamide compounds (since hydrochlorothiazide is a sulfonamide-containing drug), or to any of the excipients.
- Severe renal impairment (see sections "Special precautions for use", "Pharmacological properties").
- Persistent hypokalemia, hypercalcemia, hyponatremia, and symptomatic hyperuricemia.
- Severe hepatic impairment, cholestasis, and obstructive biliary disorders (see section "Pharmacological properties").
- Pregnancy or planned pregnancy. If pregnancy is confirmed during treatment with this medicinal product, it must be discontinued immediately and replaced with another medicinal product permitted for use during pregnancy (see sections "Special precautions for use", "Use during pregnancy or lactation").
- Concomitant use of Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) and drugs containing aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m²) (see sections "Interaction with other medicinal products and other forms of interaction", "Pharmacological properties").
Due to the presence of amlodipine as an active ingredient, Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) is contraindicated in patients with:
- Shock (including cardiogenic shock);
- Severe arterial hypotension;
- Obstruction of blood flow from the left ventricle (e.g., severe aortic stenosis);
- Hemodynamically unstable heart failure following acute myocardial infarction.
Interaction with other medicinal products and other forms of interaction.
Concomitant use not recommended
Lithium preparations
Concomitant use of lithium with angiotensin-converting enzyme (ACE) inhibitors and sometimes with angiotensin II receptor blockers has been associated with reversible increases in serum lithium concentration and lithium toxicity. In addition, thiazides reduce renal clearance of lithium, thereby increasing the risk of lithium toxicity during hydrochlorothiazide treatment. Therefore, concomitant use of Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) with lithium is not recommended. In patients who require concomitant administration of these drugs, serum lithium concentrations should be closely monitored during treatment.
Concomitant use with the following medicinal products requires caution
Baclofen
May enhance the antihypertensive effect.
Nonsteroidal anti-inflammatory drugs (NSAIDs)
NSAIDs (e.g., acetylsalicylic acid (> 3 g/day), COX-2 inhibitors, and nonselective NSAIDs) may attenuate the antihypertensive effect of thiazide diuretics and angiotensin II receptor blockers. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with renal impairment), concomitant use of angiotensin II receptor antagonists and cyclooxygenase inhibitors may lead to further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, this combination should be used with caution, especially in elderly patients. Adequate hydration of patients is recommended. Renal function should be monitored after initiation of concomitant therapy and periodically during treatment.
Considerations for concomitant use
Amifostine
May enhance antihypertensive effect.
Other antihypertensive agents
The antihypertensive effect of Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) may be enhanced when used concomitantly with other antihypertensive drugs.
Ethanol, barbiturates, narcotic analgesics, and antidepressants
May enhance symptoms of orthostatic hypotension.
Potential interactions with olmesartan medoxomil
Concomitant use not recommended
ACE inhibitors, angiotensin II receptor blockers, or aliskiren
Clinical trial data have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combining ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with a higher incidence of adverse outcomes such as hypotension, hyperkalemia, and reduced renal function (including acute renal failure), compared to using a single RAAS-acting agent.
Medicinal products affecting blood potassium concentration
Concomitant use of potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other medicinal products that may increase serum potassium levels (e.g., heparin, ACE inhibitors) may lead to increased potassium levels in blood (see section "Special precautions for use"). Monitoring of serum potassium levels is recommended when medicinal products affecting potassium levels are prescribed in combination with Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10).
Additional information
Bile acid sequestrant drug colesevelam
Concomitant use of the bile acid sequestrant colesevelam hydrochloride reduces systemic exposure and peak plasma concentration of olmesartan, as well as its elimination half-life. Administration of olmesartan medoxomil at least 4 hours before colesevelam hydrochloride reduces the effect of this drug interaction. Administration of olmesartan medoxomil at least 4 hours before colesevelam hydrochloride should be considered (see section "Pharmacological properties").
After treatment with an antacid (aluminum hydroxide, magnesium hydroxide), a moderate decrease in olmesartan bioavailability was observed.
Olmesartan medoxomil has no significant effect on the pharmacokinetics or pharmacodynamics of warfarin or on the pharmacokinetics of digoxin.
Concomitant administration of olmesartan medoxomil and pravastatin has no clinically significant effect on the pharmacokinetics of either drug in healthy volunteers.
In in vitro studies, olmesartan did not show clinically significant inhibition of human cytochrome P450 isoenzymes 1A1/2, 2A6, 2C8/9, 2C19, 2D6, 2E1, and 3A4; olmesartan showed either minimal inducing effects or no effect at all on animal cytochrome P450 isoenzymes. Therefore, clinically significant interactions between olmesartan and medicinal products metabolized by the aforementioned cytochrome P450 isoenzymes are not expected.
Potential interactions with amlodipine
Concomitant use requiring caution
Effect of other medicinal products on amlodipine
CYP3A4 inhibitors
Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil, or diltiazem) may lead to a significant increase in amlodipine exposure. The clinical manifestation of these pharmacokinetic variations may be more pronounced in elderly patients. Therefore, clinical monitoring and dose adjustment may be required.
CYP3A4 inducers
Concomitant use with CYP3A4 inducers may reduce amlodipine plasma concentrations. Therefore, careful monitoring of the patient and dose adjustment are necessary during and after concomitant use of amlodipine with CYP3A4 inducers (such as rifampicin, St. John's wort).
Consumption of amlodipine with grapefruit or grapefruit juice is not recommended, as it may increase the bioavailability of the drug in some patients, resulting in enhanced hypotensive effects.
Dantrolene (infusion)
In laboratory animal studies, ventricular fibrillation and cardiovascular collapse with fatal outcome were observed after verapamil administration followed by intravenous dantrolene, associated with hyperkalemia. Due to the risk of hyperkalemia in patients predisposed to malignant hyperthermia or during treatment of malignant hyperthermia, concomitant use of calcium channel blockers such as amlodipine should be avoided.
Effect of amlodipine on other medicinal products
The antihypertensive effect of amlodipine is additive to the antihypertensive effect of other antihypertensive drugs.
In clinical drug interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin, or warfarin.
Simvastatin
Concomitant administration of multiple doses of amlodipine (10 mg) and simvastatin (80 mg) results in a 77% increase in simvastatin exposure compared to simvastatin alone. The simvastatin dose in patients taking amlodipine should not exceed 20 mg daily.
Tacrolimus
There is a risk of increased blood levels of tacrolimus when used concomitantly with amlodipine. To avoid tacrolimus toxicity during concomitant use with amlodipine, regular monitoring of tacrolimus blood levels and dose adjustment if necessary are required.
mTOR inhibitors (mammalian target of rapamycin)
mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are CYP3A substrates. Amlodipine is a weak CYP3A inhibitor. Concomitant use of mTOR inhibitors with amlodipine may increase their effects.
Cyclosporine
In a prospective study in kidney transplant patients, cyclosporine levels increased by an average of 40% when used concomitantly with amlodipine. Concomitant use of Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) and cyclosporine increases the systemic effect of the latter. Monitoring of cyclosporine levels and dose adjustment if necessary are required during such treatment.
Potential interactions with hydrochlorothiazide
Concomitant use not recommended
Medicinal products affecting blood potassium concentration
The hypokalemic effect of hydrochlorothiazide may be enhanced when used concomitantly with other medicinal products causing potassium loss and hypokalemia (e.g., potassium-wasting diuretics, laxatives, corticosteroids, ACTH, amphotericin, carbenoxolone, sodium penicillin G, and salicylate derivatives). Therefore, concomitant use of hydrochlorothiazide with these drugs is not recommended.
Concomitant use requiring special attention
Calcium salts
Thiazide diuretics may increase serum calcium concentration by reducing calcium excretion. If calcium supplements are necessary, serum calcium levels should be monitored and calcium dosage adjusted accordingly.
Cholestyramine and colestipol resins
In the presence of anion-exchange resins, absorption of hydrochlorothiazide from the gastrointestinal tract is impaired.
Cardiac glycosides
Use of cardiac glycosides increases the risk of arrhythmias due to hypokalemia and hypomagnesemia induced by thiazides.
Medicinal products causing changes in serum potassium levels
Hypokalemia is a predisposing factor for the development of torsades de pointes (ventricular tachycardia). Periodic monitoring of serum potassium levels and ECG is recommended when Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) is used concomitantly with medicinal products causing disturbances in serum potassium levels (e.g., glycosides and antiarrhythmics) and medicinal products causing torsades de pointes (including certain antiarrhythmics):
- Class Ia antiarrhythmics (e.g., quinidine, hydroquinidine, disopyramide);
- Class III antiarrhythmics (e.g., amiodarone, sotalol, dofetilide, ibutilide);
- Certain antipsychotics (e.g., thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol);
- Other medicinal products (e.g., bepridil, cisapride, difemanil, erythromycin IV, halofantrine, mizolastine, pentamidine, sparfloxacin, terfenadine, vinpocetine IV).
Non-depolarizing skeletal muscle relaxants (e.g., tubocurarine)
Hydrochlorothiazide may enhance the efficacy of non-depolarizing skeletal muscle relaxants.
Anticholinergic agents (e.g., atropine, biperiden)
By reducing gastrointestinal motility and gastric emptying rate, anticholinergic agents may increase the bioavailability of thiazide diuretics.
Antidiabetic medicinal products (oral agents and insulin)
Thiazide therapy may affect glucose tolerance. Adjustment of antidiabetic drug dosage may be necessary (see section "Special precautions for use").
Metformin
Metformin should be used with caution due to the risk of lactic acidosis caused by functional renal impairment, which may occasionally occur with hydrochlorothiazide use.
Beta-blockers and diazoxide
The hyperglycemic effect of beta-blockers and diazoxide may be enhanced by thiazides.
Pressor amines (e.g., noradrenaline)
The effectiveness of pressor amines may be reduced.
Medicinal products used for gout treatment (probenecid, sulfinpyrazone, and allopurinol)
Since hydrochlorothiazide may occasionally increase serum uric acid concentration, dosage adjustment of uricosuric agents used for gout treatment may be necessary. Additionally, the dosage of probenecid or sulfinpyrazone may occasionally need to be increased. When allopurinol is used concomitantly with thiazides, the frequency of allergic reactions to allopurinol may increase.
Amantadine
Thiazides may increase the risk of adverse reactions caused by amantadine.
Cytostatics (e.g., cyclophosphamide, methotrexate)
Thiazides may reduce renal excretion of antineoplastic agents and enhance their myelosuppressive effects.
Salicylates
When salicylates are taken in high doses, hydrochlorothiazide may enhance their toxic effects on the central nervous system.
Methyldopa
Publications have described isolated cases of hemolytic anemia associated with concomitant use of hydrochlorothiazide and methyldopa.
Cyclosporine
Concomitant use of thiazides with cyclosporine may increase the risk of hyperuricemia and complications similar to gout.
Tetracycline
Concomitant use of thiazides with tetracycline increases the risk of tetracycline-induced uremia. This effect likely does not apply to doxycycline.
Special precautions for use.
Patients with hypovolemia or sodium deficiency
In patients with reduced circulating blood volume and/or low sodium levels due to intensive diuretic therapy, low-salt diet, diarrhea, or vomiting, clinically significant arterial hypotension may occur, especially after the first dose of the drug. Before initiating treatment with Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10), the above conditions should be corrected.
Other conditions associated with activation of the renin-angiotensin-aldosterone system (RAAS)
Patients in whom vascular tone and renal function are highly dependent on the activity of the renin-angiotensin-aldosterone system (e.g., in severe congestive heart failure or renal pathology, including renal artery stenosis) may respond to drugs affecting this system with acute arterial hypotension, azotemia, oliguria, or in rare cases, acute renal failure.
Renovascular hypertension
The use of drugs affecting the renin-angiotensin-aldosterone system in patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney is associated with an increased risk of severe arterial hypotension and renal failure.
Renal function impairment and kidney transplantation
When using Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) in patients with renal impairment, periodic monitoring of serum potassium and creatinine levels is recommended. The use of Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) is not recommended in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see sections "Dosage and administration", "Contraindications", "Pharmacological properties").
Diuretic-induced azotemia may develop in patients with renal dysfunction.
If signs of worsening renal function occur, therapy should be reassessed and discontinuation of diuretic treatment considered.
There is no experience with the use of Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) in patients who have recently undergone kidney transplantation or have end-stage renal failure (creatinine clearance < 12 mL/min).
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
Concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of arterial hypotension, hyperkalemia, and reduced renal function (including acute renal failure). Therefore, dual RAAS blockade with concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended (see sections "Interaction with other medicinal products and other forms of interaction", "Pharmacological properties").
If dual blockade therapy is absolutely necessary, it should be administered only under specialist supervision with careful monitoring of renal function, electrolyte levels, and blood pressure.
Patients with diabetic nephropathy should not receive concomitant treatment with ACE inhibitors and angiotensin II receptor blockers.
Hepatic impairment
In patients with hepatic impairment, plasma levels of olmesartan medoxomil and amlodipine are increased (see section "Pharmacological properties"). Additionally, in patients with hepatic impairment or progressive liver disease, minor disturbances in fluid and electrolyte balance due to thiazide therapy may precipitate hepatic coma. Therefore, Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) should be used with caution in patients with mild to moderate hepatic impairment. For patients with moderate hepatic impairment, the dose of olmesartan medoxomil should not exceed 20 mg (see section "Dosage and administration").
Amlodipine should be initiated at the lowest dose in patients with hepatic impairment, and special attention should be paid to monitoring their condition both at the beginning of treatment and during dose escalation.
The use of Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) is contraindicated in patients with severe hepatic impairment, cholestasis, or biliary obstruction (see section "Contraindications").
Aortic valve stenosis and mitral stenosis, hypertrophic obstructive cardiomyopathy
As with other vasodilators, olmesartan medoxomil should be used cautiously in patients with aortic valve stenosis or mitral stenosis, as well as in obstructive hypertrophic cardiomyopathy.
Primary hyperaldosteronism
Patients with primary hyperaldosteronism generally do not respond to antihypertensive agents that inhibit the renin-angiotensin system. Therefore, Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) is not recommended for such patients.
Metabolic and endocrine effects
Thiazide group drugs may impair glucose tolerance. Patients with diabetes may require adjustment of insulin or oral hypoglycemic agent doses (see section "Interaction with other medicinal products and other forms of interaction"). Thiazide use may unmask latent diabetes mellitus.
Thiazide diuretics may cause adverse reactions such as increased cholesterol and triglyceride levels. In some cases, thiazide use may lead to hyperuricemia or gout.
Electrolyte disturbances
As with any diuretic, serum electrolyte concentrations should be monitored periodically during hydrochlorothiazide use. Thiazide diuretics, including hydrochlorothiazide, may cause disturbances in fluid and electrolyte balance (including hypokalemia, hyponatremia, and hypochloremic alkalosis). Signs of fluid and electrolyte imbalance include dry mouth, thirst, weakness, prolonged sleep, drowsiness, restlessness, muscle pain or cramps, muscle fatigue, arterial hypotension, oliguria, tachycardia, and gastrointestinal disturbances, including nausea and vomiting (see section "Undesirable effects"). The risk of hypokalemia is highest in patients with liver cirrhosis, marked diuresis, inadequate oral electrolyte intake, or concomitant use of corticosteroids and ACTH (see section "Interaction with other medicinal products and other forms of interaction").
On the other hand, due to blockade of angiotensin II receptors (AT1) by olmesartan medoxomil, a component of Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10), hyperkalemia may occur, particularly in patients with renal impairment and/or heart failure, as well as in patients with diabetes mellitus. Serum potassium levels should be appropriately monitored in these patients. Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) should be used cautiously when co-administered with potassium supplements, potassium-sparing diuretics, potassium-containing salt substitutes, and other drugs that may increase serum potassium levels (e.g., heparin), and potassium levels should be frequently monitored (see section "Interaction with other medicinal products and other forms of interaction").
There is no evidence that olmesartan medoxomil can mitigate or prevent diuretic-induced hyponatremia. Chloride deficiency is usually mild and does not require specific treatment. Thiazides may reduce urinary calcium excretion and cause mild and transient elevation of serum calcium concentration in the absence of any calcium metabolism disorders. Hypercalcemia may indicate occult hyperparathyroidism. Thiazides should be discontinued before parathyroid function testing. Thiazides enhance urinary magnesium excretion, which may lead to hypomagnesemia. Hyponatremia of dilution may occur in patients with edema during hot weather.
Lithium preparations
As with other medicinal products containing angiotensin II receptor blockers in combination with thiazides, Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) is not recommended for concomitant use with lithium preparations (see section "Interaction with other medicinal products and other forms of interaction").
Heart failure
Due to inhibition of the renin-angiotensin-aldosterone system, changes in renal function may occur in susceptible patients.
In patients with severe heart failure, in whom renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors and angiotensin receptor antagonists may be associated with oliguria and/or progressive azotemia and (rarely) acute renal failure with potentially fatal outcome.
Treatment of patients with heart failure requires special attention. In a long-term placebo-controlled study of amlodipine in patients with severe heart failure (NYHA III and IV), the number of reports of pulmonary edema was higher in the amlodipine group compared to the placebo group (see section "Pharmacological properties"). Calcium channel blockers, including amlodipine, should be used cautiously in patients with congestive heart failure, as these drugs may increase the risk of future cardiovascular complications and mortality.
Sprue-like enteropathy
In very rare cases, severe chronic diarrhea with significant weight loss has been reported, developing several months or years after initiation of treatment in patients taking olmesartan; the cause is likely a localized delayed hypersensitivity reaction. Intestinal mucosal biopsies in such patients often show villous atrophy. If such symptoms occur in a patient during olmesartan treatment and other probable causes can be excluded, olmesartan therapy should be discontinued immediately and not resumed. If diarrhea does not resolve within one week after stopping the drug, a specialist (e.g., a gastroenterologist) should be consulted.
Choroidal effusion, acute myopia, and secondary angle-closure glaucoma
Hydrochlorothiazide is a sulfonamide and may cause idiosyncratic reactions leading to choroidal effusion with visual field defects, acute transient myopia, and acute attacks of angle-closure glaucoma. Symptoms include acute onset of myopia or eye pain and typically occur within hours to weeks after starting treatment. Untreated acute angle-closure glaucoma may lead to permanent vision loss. Hydrochlorothiazide should be discontinued as soon as possible. If intraocular pressure cannot be controlled, urgent medical or surgical treatment may be required. A history of allergy to sulfonamides or penicillin may be a risk factor for the development of angle-closure glaucoma (see section "Undesirable effects").
Pregnancy
Treatment with angiotensin II receptor antagonists should not be initiated during pregnancy. If antihypertensive therapy is considered necessary, pregnant women or women planning pregnancy should switch to an alternative therapy with a proven safety profile during pregnancy. Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) should not be used in pregnant women or women who are planning to become pregnant. If pregnancy is confirmed during treatment with this drug, its use must be immediately discontinued and replaced with another medicinal product approved for use in pregnancy (see sections "Contraindications" and "Use in pregnancy or lactation").
Children
Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) is not indicated for use in children (under 18 years of age).
Elderly patients
Dosage increases in elderly patients should be made with caution (see section "Pharmacological properties").
Photosensitization
Cases of photosensitivity have been reported during treatment with thiazide diuretics (see section "Undesirable effects"). If such a reaction occurs during treatment with Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10), the drug should be discontinued. When resuming diuretic therapy, exposure to direct sunlight and artificial UV radiation should be avoided.
Non-melanoma skin cancer
Results from two Danish pharmacoepidemiological studies showed an increased risk of non-melanoma skin cancer and lip cancer (basal cell carcinoma, squamous cell carcinoma) associated with cumulative hydrochlorothiazide (HCTZ) dose. Photosensitization during HCTZ use may contribute to the development of non-melanoma skin cancer.
Patients taking HCTZ should be informed about the risk of non-melanoma skin cancer or lip cancer and advised to regularly check their skin for new lesions or any suspicious skin changes. Patients should be advised to limit exposure to sunlight and ultraviolet radiation and use appropriate protection when exposed to sunlight or UV radiation to minimize skin cancer risk. Suspicious skin lesions should be evaluated, possibly with histological examination of biopsy material. Additionally, HCTZ-containing drugs should be prescribed cautiously in patients with a history of non-melanoma skin cancer (see section "Undesirable effects").
Acute respiratory toxicity
Very rare severe cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS), have been reported after hydrochlorothiazide administration. Pulmonary edema typically develops within minutes or hours after hydrochlorothiazide intake. Initial symptoms include dyspnea, fever, pulmonary deterioration, and hypotension. If ARDS is suspected, Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) should be discontinued and appropriate treatment initiated. Hydrochlorothiazide should not be prescribed to patients who previously experienced ARDS after hydrochlorothiazide use.
Other precautions
Excessive reduction in blood pressure in patients with generalized atherosclerosis, ischemic heart disease, or cerebral ischemia may lead to myocardial infarction or stroke.
The risk of allergic reactions to hydrochlorothiazide is higher in patients with a history of allergy or bronchial asthma, although such reactions may also occur in patients without such history.
According to scientific literature, thiazide diuretics may provoke exacerbation or activation of systemic lupus erythematosus.
As with other angiotensin II antagonists, the antihypertensive effect of Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) may be somewhat lower in black patients compared to other racial groups, although this effect was not observed in three studies involving black patients (30%) (see section "Pharmacological properties").
This medicinal product contains less than 1 mmol sodium (23 mg) per film-coated tablet, i.e., it is considered sodium-free.
Use during pregnancy or breastfeeding
Pregnancy
Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) should not be used in pregnant women or women planning to become pregnant. If pregnancy is confirmed during treatment with this medicinal product, its use must be immediately discontinued and replaced with another medicinal product approved for use in pregnancy (see sections "Contraindications", "Special precautions for use").
Olmesartan medoxomil
Epidemiological data on teratogenic risk of ACE inhibitors in the first trimester of pregnancy do not allow definitive conclusions, but a small risk of such effects cannot be completely excluded. A similar risk may be assumed with angiotensin II receptor antagonists, although controlled epidemiological studies of these drugs have not been conducted. Women planning pregnancy should switch to other antihypertensive drugs with a proven safety profile during pregnancy unless there is an urgent need for angiotensin II receptor antagonists. Upon detection of pregnancy, angiotensin II receptor antagonists should be discontinued immediately and alternative treatment initiated if necessary.
In the second and third trimesters, angiotensin II receptor antagonists have toxic effects on the fetus (impaired renal function, oligohydramnios, delayed skull ossification) and the newborn (renal failure, arterial hypotension, hyperkalemia) (see section "Preclinical safety data").
If angiotensin II receptor antagonists are used from the second trimester of pregnancy, monitoring of fetal renal function and skull ossification by ultrasound is required. Newborns whose mothers received angiotensin II receptor antagonists should be monitored for possible arterial hypotension (see sections "Contraindications" and "Special precautions for use").
Hydrochlorothiazide
Experience with hydrochlorothiazide use during pregnancy, especially in the first trimester, is limited. Experimental animal studies are insufficient. Hydrochlorothiazide crosses the placental barrier. Due to its mechanism of action, hydrochlorothiazide use in the second and third trimesters of pregnancy may impair fetoplacental circulation and adversely affect the fetus and newborn, causing jaundice, electrolyte disturbances, and thrombocytopenia.
Hydrochlorothiazide is not indicated for the treatment of edema in pregnancy, gestational hypertension, or preeclampsia, as it may reduce plasma volume and cause placental hypoperfusion without providing adequate therapeutic effect.
Hydrochlorothiazide is also not recommended for the treatment of essential hypertension in pregnancy, except in exceptional cases where other drugs cannot be used.
Amlodipine
Data from limited observations in pregnant women do not indicate that amlodipine or other calcium channel antagonists have harmful effects on fetal health. However, there is a risk of prolonged labor.
Lactation
Due to lack of information on the use of Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) during lactation, this medicinal product is not recommended for use in breastfeeding women. Alternative treatments with a better-established safety profile during lactation are recommended, especially for women breastfeeding newborns or preterm infants.
Olmesartan passes into the milk of lactating rats. However, it is unknown whether olmesartan passes into human breast milk.
Amlodipine passes into human breast milk. The fraction of maternal dose received by the infant is estimated at 3–7% (interquartile range), with a maximum of 15%. The effect of amlodipine on infants is unknown.
Hydrochlorothiazide passes into breast milk in small amounts. The use of thiazides in high doses causing strong diuresis may interfere with breast milk production. The use of Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) during breastfeeding is not recommended. If Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) is used during breastfeeding, the dose should be as low as possible.
Fertility
Cases of reversible biochemical changes in the sperm head have been reported in some patients taking calcium channel blockers. Clinical data on the potential impact of amlodipine on fertility are insufficient. An adverse effect on male fertility was observed in a rat study (see section "Pharmacological properties").
Ability to affect reaction speed when driving or operating machinery
No studies have been conducted on the effect on reaction speed when driving or operating machinery.
However, it should be noted that patients receiving antihypertensive therapy may occasionally experience dizziness, headache, nausea, or fatigue, which may impair their reaction ability. Caution is advised, especially at the beginning of treatment.
Method of Administration and Dosage
Adults
Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) tablets should be taken once daily, independently of food intake.
The tablet should be swallowed with sufficient liquid (e.g., a glass of water). The tablet must not be chewed. The medication should be taken every day at the same time.
Additional Therapy
Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) may be used in patients whose arterial blood pressure is not adequately controlled with olmesartan medoxomil 20 mg and amlodipine 5 mg as a two-component combination.
Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) may be used in patients whose arterial blood pressure is not adequately controlled with Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10).
Before switching to the three-component combination, gradual titration of individual component dosages is recommended. If clinically appropriate, direct substitution of the two-component combination with the three-component combination may be considered.
Substitution Therapy
Patients who are concurrently receiving stable doses of olmesartan medoxomil, amlodipine, and hydrochlorothiazide as two-component (olmesartan medoxomil and amlodipine or olmesartan medoxomil and hydrochlorothiazide) and single-component (hydrochlorothiazide or amlodipine) medicinal products may be switched to Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) containing the same component doses.
The maximum daily dose of Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) is 40 mg/12.5 mg/10 mg.
Elderly Patients (aged 65 years and older)
Elderly patients should be treated with caution, with more frequent monitoring of blood pressure, especially when receiving the maximum dose of Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) of 40 mg/12.5 mg/10 mg daily.
Dose escalation in elderly patients should be performed cautiously (see sections "Special Warnings and Precautions for Use", "Pharmacological Properties").
Information on the use of Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) in patients aged 75 years and older is very limited. Extreme caution is required, including more frequent blood pressure monitoring.
Renal Impairment
The maximum dose for patients with mild to moderate renal impairment (creatinine clearance 30–60 mL/min) is 20 mg/5 mg/12.5 mg once daily due to limited experience with 40 mg of olmesartan medoxomil in this patient group.
Patients with moderate renal impairment should be monitored for serum potassium and creatinine concentrations.
Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see sections "Contraindications", "Special Warnings and Precautions for Use", "Pharmacological Properties").
Hepatic Impairment
Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) should be used with caution in patients with mild hepatic impairment (see sections "Special Warnings and Precautions for Use", "Pharmacological Properties").
For patients with moderate hepatic impairment, the maximum dose should not exceed 20 mg/5 mg/12.5 mg once daily. Careful monitoring of blood pressure and renal function is recommended in patients with hepatic impairment.
As with all calcium channel antagonists, the elimination half-life of amlodipine is prolonged in patients with hepatic dysfunction; dosage recommendations have not been established. Therefore, Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) should be prescribed with caution in such patients. The pharmacokinetics of amlodipine in patients with severe hepatic impairment have not been studied. Amlodipine administration in patients with severe hepatic impairment should be initiated at the lowest dose with gradual dose escalation.
Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) is contraindicated in patients with severe hepatic impairment, cholestasis, or biliary obstruction (see section "Contraindications").
Children
Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) is not recommended for use in children (under 18 years of age) due to insufficient data on safety and efficacy.
Overdose
Symptoms
The maximum recommended daily dose of Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) is 40 mg/12.5 mg/10 mg once daily. There is no information on overdose with Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) in humans. The most likely effect of overdose is hypotension.
The most likely effects of olmesartan medoxomil overdose are hypotension and tachycardia; bradycardia may occur if parasympathetic (vagal) stimulation takes place.
Overdose with amlodipine may lead to excessive peripheral vasodilation resulting in marked hypotension and possibly reflex tachycardia. Marked and potentially prolonged systemic hypotension, including shock with fatal outcome, has been reported.
Rare cases of non-cardiogenic pulmonary edema have been reported following amlodipine overdose, which may manifest with delayed onset (24–48 hours after ingestion) and may require mechanical ventilation. Early resuscitation measures (including fluid loading) to maintain perfusion and cardiac output may act as triggering factors.
Hydrochlorothiazide overdose is associated with electrolyte imbalance (hypokalemia, hypochloremia) and dehydration due to excessive diuresis.
The most common symptoms of overdose are nausea and drowsiness. Hypokalemia may lead to muscle cramps and/or severe cardiac arrhythmias, particularly when combined with digitalis glycosides or certain antiarrhythmic drugs.
Treatment
In case of Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) overdose, treatment is symptomatic and supportive, and depends on the time elapsed since ingestion and the severity of symptoms.
If ingestion was recent, gastric lavage may be considered. In healthy volunteers, administration of activated charcoal immediately or within 2 hours after amlodipine intake significantly reduces its absorption.
Clinically significant hypotension caused by Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) overdose requires active cardiovascular support, including careful monitoring of cardiac and pulmonary function, placing the patient in a supine position with elevated legs, and monitoring of circulating fluid volume and diuresis. A vasopressor may be useful to restore vascular tone and arterial pressure, provided there are no contraindications to its use. Intravenous calcium gluconate may be beneficial in reversing calcium channel blockade effects.
Serum electrolyte levels and creatinine should be monitored frequently. If hypotension occurs, the patient should be placed in a supine position and receive volume replacement with saline solutions.
Since amlodipine is highly protein-bound, dialysis is unlikely to be beneficial.
The extent of olmesartan and hydrochlorothiazide removal by hemodialysis has not been established.
Adverse Reactions
The safety of Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) was evaluated in clinical trials involving 7,826 patients who received olmesartan medoxomil in combination with amlodipine and hydrochlorothiazide.
Adverse events observed during clinical studies and post-marketing safety surveillance, as well as adverse reactions reported spontaneously, are listed in the table below (Table 1) for Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10), and also for its individual components—olmesartan medoxomil, amlodipine, and hydrochlorothiazide—based on the known safety profiles of the individual components.
During treatment with Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10), the most commonly reported adverse reactions are peripheral edema, headache, and dizziness.
The following classification was used to indicate the frequency of adverse reactions: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000), and not known (cannot be estimated based on available data).
Table 1
Adverse reactions associated with the use of Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10) and its individual components
| MedDRA Organ system classes |
Adverse reaction |
Frequency |
|||
| Olmesartan medoxomil/amlodipine/hydrochlorothiazide |
Olmesartan |
Amlodipine |
Hydrochlorothiazide |
||
| Infections and infestations |
Upper respiratory tract infections |
Common |
|||
| Nasopharyngitis |
Common |
||||
| Urinary tract infections |
Common |
Common |
|||
| Sialadenitis |
Uncommon |
||||
| Neoplasms benign, malignant and unspecified (including cysts and polyps) |
Non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma) |
Frequency unknown |
|||
| Blood and lymphatic system disorders |
Leukopenia |
Very rare |
Uncommon |
||
| Thrombocytopenia |
Uncommon |
Very rare |
Uncommon |
||
| Bone marrow suppression |
Uncommon |
||||
| Neutropenia/ agranulocytosis |
Uncommon |
||||
| Hemolytic anemia |
Uncommon |
||||
| Aplastic anemia |
Uncommon |
||||
| Immune system disorders |
Anaphylactic reaction |
Uncommon |
|||
| Drug hypersensitivity |
Very rare |
||||
| Metabolism and nutrition disorders |
Hyperkalemia |
Uncommon |
Uncommon |
||
| Hypokalemia |
Uncommon |
Common |
|||
| Anorexia |
Uncommon |
||||
| Glucosuria |
Common |
||||
| Hypercalcemia |
Common |
||||
| Hypoglycemia |
Very rare |
Common |
|||
| Hypomagnesemia |
Common |
||||
| Hypnatremia |
Common |
||||
| Hypochloremia |
Common |
||||
| Hypertriglyceridemia |
Common |
Very common |
|||
| Hypercholesterolemia |
Very common |
||||
| Hyperuricemia |
Common |
Very common |
|||
| Hypochloremic alkalosis |
Very rare |
||||
| Hyperamylasemia |
Common |
||||
| Endocrine disorders |
Syndrome of inappropriate antidiuretic hormone secretion (SIADH) |
Frequency unknown |
|||
| Psychiatric disorders |
Confusion |
Uncommon |
Common |
||
| Depression |
Uncommon |
Uncommon |
|||
| Apathy |
Uncommon |
||||
| Irritability |
Uncommon |
||||
| Agitation |
Uncommon |
||||
| Mood changes (including anxiety) |
Uncommon |
||||
| Sleep disorders (including insomnia) |
Uncommon |
Uncommon |
|||
| Nervous system disorders |
Dizziness |
Common |
Common |
Common |
Common |
| Headache |
Common |
Common |
Common |
Uncommon |
|
| Postural dizziness |
Uncommon |
||||
| Loss of consciousness |
Uncommon |
||||
| Dysgeusia |
Uncommon |
||||
| Hypertonia |
Very rare |
||||
| Hypoesthesia |
Uncommon |
||||
| Paraesthesia |
Uncommon |
Uncommon |
|||
| Peripheral neuropathy |
Very rare |
||||
| Somnolence |
Common |
||||
| Loss of consciousness |
Uncommon |
||||
| Convulsions |
Uncommon |
||||
| Loss of appetite |
Uncommon |
||||
| Tremor |
Uncommon |
||||
| Extrapyramidal disorders |
Frequency unknown |
||||
| Eye disorders |
Visual disturbances (including diplopia, blurred vision) |
Common |
Uncommon |
||
| Decreased lacrimation |
Uncommon |
||||
| Acute myopia |
Uncommon |
||||
| Xanthopsia |
Uncommon |
||||
| Acute myopia, acute angle-closure glaucoma (see section "Special warnings and precautions for use") |
Frequency unknown |
||||
| Choroidal effusion |
Frequency unknown |
||||
| Ear and labyrinth disorders |
Vertigo |
Uncommon |
Uncommon |
Uncommon |
|
| Tinnitus |
Uncommon |
||||
| Cardiac disorders |
Pounding heartbeat |
Common |
Common |
||
| Tachycardia |
Uncommon |
||||
| Myocardial infarction |
Very rare |
||||
| Arrhythmias (including bradycardia, ventricular tachycardia, atrial fibrillation) |
Uncommon |
Uncommon |
|||
| Angina pectoris |
Uncommon |
Uncommon including worsening of angina |
|||
| Vascular disorders |
Arterial hypotension |
Common |
Uncommon |
Uncommon |
|
| Flushing |
Uncommon |
Common |
|||
| Orthostatic hypotension |
Uncommon |
||||
| Vasculitis (including necrotizing vasculitis) |
Very rare |
Uncommon |
|||
| Thrombosis |
Uncommon |
||||
| Embolism |
Uncommon |
||||
| Respiratory, thoracic and mediastinal disorders |
Cough |
Uncommon |
Common |
Uncommon |
|
| Bronchitis |
Common |
||||
| Dyspnea |
Common |
Uncommon |
|||
| Pharyngitis |
Common |
||||
| Rhinitis |
Common |
Uncommon |
|||
| Acute interstitial pneumonia |
Uncommon |
||||
| Respiratory distress |
Uncommon |
||||
| Lung edema |
Uncommon |
||||
| Acute respiratory distress syndrome (ARDS) (see section "Special warnings and precautions for use") |
Very rare |
||||
| Gastrointestinal disorders |
Diarrhea |
Common |
Common |
Common |
|
| Nausea |
Common |
Common |
Common |
Common |
|
| Constipation |
Common |
Common |
|||
| Dry mouth |
Uncommon |
Uncommon |
|||
| Abdominal pain |
Common |
Common |
Common |
||
| Intestinal function disorders (including constipation and diarrhea) |
Common |
||||
| Flatulence |
Common |
||||
| Digestive disorders |
Common |
Common |
|||
| Gastritis |
Very rare |
||||
| Stomach irritation |
Common |
||||
| Gastroenteritis |
Common |
||||
| Gingival hyperplasia |
Very rare |
||||
| Paralytic ileus |
Very rare |
||||
| Pancreatitis |
Very rare |
Uncommon |
|||
| Vomiting |
Uncommon |
Uncommon |
Common |
||
| Sprue-like enteropathy (see section "Special warnings and precautions for use") |
Very rare |
||||
| Hepatobiliary disorders |
Hepatitis |
Very rare |
|||
| Jaundice (cholestatic jaundice) |
Very rare |
Uncommon |
|||
| Acute cholecystitis |
Uncommon |
||||
| Autoimmune hepatitis* |
Unknown |
||||
| Skin and subcutaneous tissue disorders |
Alopecia |
Uncommon |
|||
| Angioedema |
Uncommon |
Very rare |
|||
| Allergic dermatitis |
Uncommon |
||||
| Multiform erythema |
Very rare |
||||
| Erythema |
Uncommon |
||||
| Reactions resembling cutaneous manifestations of systemic lupus erythematosus |
Uncommon |
||||
| Exanthema |
Uncommon |
Uncommon |
|||
| Exfoliative dermatitis |
Very rare |
||||
| Increased sweating |
Uncommon |
||||
| Photosensitivity |
Very rare |
Uncommon |
|||
| Pruritus |
Uncommon |
Uncommon |
Uncommon |
||
| Purpura |
Uncommon |
Uncommon |
|||
| Quincke's edema |
Very rare |
||||
| Rash |
Uncommon |
Uncommon |
Uncommon |
||
| Exacerbation of cutaneous form of systemic lupus erythematosus |
Uncommon |
||||
| Toxic epidermal necrolysis |
Frequency unknown |
Uncommon |
|||
| Skin color changes |
Uncommon |
||||
| Stevens-Johnson syndrome |
Very rare |
||||
| Urticaria |
Uncommon |
Uncommon |
Uncommon |
||
| Musculoskeletal and connective tissue disorders |
Muscle spasms |
Common |
Uncommon |
Common |
|
| Joint swelling |
Common |
||||
| Muscle weakness |
Uncommon |
Uncommon |
|||
| Calf swelling |
Common |
||||
| Arthralgia |
Uncommon |
||||
| Arthritis |
Common |
||||
| Back pain |
Common |
Uncommon |
|||
| Paralysis |
Uncommon |
||||
| Myalgia |
Uncommon |
Uncommon |
|||
| Bone pain |
Common |
||||
| Renal and urinary disorders |
Frequency of urination |
Common |
|||
| Increased frequency of urination |
Uncommon |
||||
| Acute renal failure |
Uncommon |
||||
| Hematuria |
Common |
||||
| Urinary disorders |
Uncommon |
||||
| Nocturia |
Uncommon |
||||
| Interstitial nephritis |
Uncommon |
||||
| Renal failure |
Uncommon |
Uncommon |
|||
| Reproductive system and breast disorders |
Erectile dysfunction |
Uncommon |
Uncommon |
Uncommon |
|
| Gynecomastia |
Uncommon |
||||
| General disorders |
Asthenia |
Common |
Uncommon |
Common |
|
| Peripheral edema |
Common |
Common |
|||
| Fatigue |
Common |
Common |
Common |
||
| Chest pain |
Common |
Uncommon |
|||
| Fever |
Uncommon |
||||
| Influenza-like symptoms |
Common |
||||
| Somnolence |
Uncommon |
||||
| Anxiety |
Uncommon |
Uncommon |
|||
| Edema |
Very common |
||||
| Pain |
Common |
Uncommon |
|||
| Facial swelling |
Uncommon |
||||
| Investigations |
Increase in blood creatinine levels |
Common |
Uncommon |
Common |
|
| Increase in blood urea levels |
Common |
Common |
Common |
||
| Increase in blood uric acid levels |
Common |
||||
| Decrease in blood potassium levels |
Uncommon |
||||
| Increase in blood gamma-glutamyltransferase levels |
Uncommon |
||||
| Increase in alanine aminotransferase activity |
Uncommon |
||||
| Increase in aspartate aminotransferase activity |
Uncommon |
||||
| Increase in liver enzymes |
Common |
Very rare (mostly in cholestasis) |
|||
| Increase in blood creatine phosphokinase levels |
Common |
||||
| Decrease in body weight |
Uncommon |
||||
| Increase in body weight |
Uncommon |
||||
* During the post-marketing period, cases of autoimmune hepatitis with a latency period ranging from several months to years have been reported, which was reversible upon discontinuation of olmesartan.
Several cases of rhabdomyolysis, temporally associated with the use of angiotensin II receptor blockers, have been reported. Extrapyramidal disorder has been reported in several patients treated with amlodipine.
Non-melanoma skin cancer
Pharmacoepidemiological studies have shown an increased risk of non-melanoma skin cancer associated with cumulative dose of hydrochlorothiazide (HCTZ) (see sections "Special precautions", "Pharmacological properties").
Adverse reactions reported in clinical trials or known from post-marketing experience with the fixed-dose combination of olmesartan medoxomil and amlodipine, but not reported with Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10), monotherapy with olmesartan medoxomil or monotherapy with amlodipine, or reported more frequently with dual combination therapy, are listed in Table 2.
Table 2
Adverse reactions during treatment with the combination of olmesartan medoxomil and amlodipine
| Organs and systems |
Frequency |
Adverse reactions |
| Immune system disorders |
Uncommon |
Hypersensitivity to the drug |
| Gastrointestinal disorders |
Uncommon |
Upper abdominal pain |
| Reproductive system and breast disorders |
Uncommon |
Decreased libido |
| General disorders |
Common |
Soft tissue edema |
| Uncommon |
Somnolence |
|
| Musculoskeletal and connective tissue disorders |
Uncommon |
Limb pain |
The adverse reactions listed in Table 3 refer to clinical studies and post-marketing use of fixed-dose combinations of olmesartan medoxomil and hydrochlorothiazide and do not pertain to the use of Olmesar NA 40/12.5/5 (Olmesar NA 40/12.5/10), monotherapy with olmesartan medoxomil or hydrochlorothiazide, or indicate a higher frequency of adverse reactions with the two-component combination.
Table 3
Adverse reactions associated with the use of the combination of olmesartan medoxomil and hydrochlorothiazide
| Organs and systems |
Frequency |
Adverse reactions |
| Neurological disorders |
Uncommon |
Disturbance of consciousness (loss of consciousness) |
| Skin and subcutaneous tissue disorders |
Uncommon |
Atopic dermatitis (eczema) |
| Musculoskeletal and connective tissue disorders |
Uncommon |
Limb pain |
| Laboratory and instrumental data |
Rare |
Slight decrease in mean hemoglobin and hematocrit levels |
Reporting of adverse reactions
Reporting of adverse reactions after registration of the medicinal product is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy of the medicinal product via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua
Shelf life. 3 years.
Storage conditions.
Store at a temperature not exceeding 25 °C in the original packaging. Keep out of reach of children.
Packaging.
10 tablets per blister, 3 or 9 blisters per cardboard box.
Prescription status. Prescription only.
Manufacturer.
Macleods Pharmaceuticals Limited.
Manufacturer's address and site of operations.
Village Thedda, P.O. Lodhiamaira, Tehsil Baddi, District Solan, Himachal Pradesh – 174101, India.